26

Thymoglobulin and Antithymocyte Globulin

DOSING AND ADMINISTRATION

CASE 34-1, QUESTION 3: How would rATG be administered and monitored in G.P.?

Both rATG and horse ATG are effective as induction therapy, although not FDA

approved, and as treatment of acute rejection. The dose of rATG ranges from 1 to 6

mg/kg but is typically 1.5 mg/kg/day, and the dose of horse ATG is 10 to 20

mg/kg/day, but is typically 15 mg/kg/day. These drugs can be diluted in 0.9% NaCl

for injection and administered for 4 to 6 hours. Both are usually infused into a highflow central vein to reduce pain, erythema, and phlebitis at the injection site.

Peripheral administration has been used successfully with rATG27 Skin testing is

recommended before horse ATG use, but not rabbit-derived rATG. Patients

previously sensitized to horse serum are at risk for an anaphylactoid reaction, but the

prevalence of anaphylaxis has diminished with improved purification of this product.

Patients with a positive pretherapy skin test could undergo desensitization, but

alternatives, such as rATG, may be substituted.

18

DOSE REGIMEN AND DURATION OF THERAPY

The first dose of rATG is usually given intraoperatively. Intraoperative

administration of rATG reduces the incidence and severity of delayed graft function

as compared with postoperative administration. Duration of therapy with rATG or

horse ATG is 3 to 10 days for induction therapy. Protocols used to treat rejection

commonly use a 7- to 10-day course of therapy. In patients such as G.P., a four-dose

prophylactic regimen has been shown to be as effective as a longer regimen.

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ADVERSE EFFECTS

A number of adverse effects have been related to the use of rabbit antithymocyte

globulin or ATG. Local phlebitis and pain usually can occur. Anaphylaxis is rare.

Chills and fever, erythema, rash, hives, pruritus, headache, leukopenia, and

thrombocytopenia are commonly encountered. Fever, chills, hypotension, nausea, and

vomiting may be caused by the release of cytokines, such as TNF and IL-6, from

lysed lymphocytes. These symptoms can be minimized by premedication with

acetaminophen and diphenhydramine before each dose.

Methylprednisolone, up to 500 mg, is given 1 hour before rabbit antithymocyte

globulin typically for the first two doses to minimize infusion reactions.

Opportunistic viral (cytomegalovirus (CMV) and Epstein–Barr virus [EBV]) and

fungal infections are the predominant delayed side effect. Susceptibility to

malignancy, such as post-transplantation lymphoproliferative disease (PTLD), is also

a concern. Because of the increased risk of CMV infection, patients are often given

oral valganciclovir or IV ganciclovir during therapy and then oral valganciclovir,

which is continued up to several months after induction.

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MONITORING

Vital signs should be monitored hourly during infusion, and WBC and platelet counts

should be monitored daily. If the patient’s WBC count drops to less than 3,000

cells/μL or if the platelet count drops to less than 100,000 cells/μL, the dose of drug

is decreased by 50% or held entirely until the counts return to desired levels. Patients

who receive rATG for the treatment of acute rejection may have doses held or

decreased based on the degree of leucopenia and thrombocytopenia; however, the

need for and response to therapy would be carefully considered in this decision.

Dosages also can be adjusted based on absolute lymphocyte counts or lymphocyte

subsets as a way of maximizing efficacy and minimizing infectious complications.

For example, the dose can be adjusted by using a target absolute T-lymphocyte count

(CD2 or CD3) of less than 25 to 50 cells/μL, particularly if used for treatment of

acute rejection. It is less common to adjust doses based on CD2 of CD3 counts when

used for induction as in G.P.’s case. Using CD2 and CD3 counts results in a lower

dose, less frequent dosing (e.g., every other day instead of daily), lower costs, and a

lower rate of viral infection. rATG produces a more profound and longer duration of

effect on lymphocytes than horse ATG; however, it does not result in a greater risk

for infection and malignancy, although still a concern.

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CASE 34-1, QUESTION 4: Could basiliximab or alemtuzumab be used as an alternative to rabbit

antithymocyte globulin?

Basiliximab is approved for use as induction therapy in kidney transplantation;

however, it is also used in other organ transplant recipients. It is administered in

combination with cyclosporine or tacrolimus and steroids with or without MMF or

sirolimus. It has a similar safety profile compared to placebo and better safety

profile than rATG. It has a limited role in high-risk populations such as G.P., or

patients with high PRA or long ischemic times,

p. 725

p. 726

delayed graft function, or patients who have received a previous transplant. In

these patients, induction with polyclonal antibodies is used in most centers. The large

initial trials with this IL-2R antibody included very few high-risk patients or

excluded them altogether. More potent agents, such as rATG, are still preferred in

high-risk patients. A prospective study comparing rATG with basiliximab in highrisk kidney transplants demonstrated that acute rejection rates were lower in patients

receiving rATG.

20 Basiliximab is often used for low-risk to intermediate-risk

patients and in patients where CNI minimization or steroid avoidance is implemented

Alemtuzumab is another alternative and is used by some centers for low- and

intermediate- to high-risk patients. It has been shown to be no less effective than

rATG in high-risk patients and more effective in reducing acute rejection than

basiliximab in low-risk patients.

28 Adverse effects include frequent and prolonged

neutropenia, lymphopenia, thrombocytopenia, anemia, nausea, vomiting, and

diarrhea. Infusion reactions can occur although it is given, as a single dose, under

anesthesia, in the operating room during the transplant. As with rATG, there is an

increased risk of opportunistic infections and malignancy. Rituximab has also been

studied as potential induction therapy in nonsensitized or ABO-compatible

transplants and found not to be very effective in this population, unlike that in ABOincompatible recipients.